Structural variants of Abeta oligomer displacing small molecules

AbstractProject Summary Cognition Therapeutics Incs mission is to develop effective therapeutics for Alzheimer s diseaseADRecent scientific discoveries have identified oligomers of the brain protein Amyloid betaA Osas toxic culprits in disease progressionCognition has identified a subset of sigmareceptor binding modulators that displace A Os from neurons and block the downstream pathological signaling that inhibits memory formationThis approach is in contrast to traditional A O intervention strategieswhich either block the expression of Abeta or clear A Os or block their formationThese compounds should prevent further A O induced damageand unmask existing memory capacity as synapses recoverThese receptor binding modulators are hypothesized to be disease modifying treatments that would be effective throughout the course of the diseaseand significantly impact the lives of the millions of Alzheimer s patientsPharmaceutical industry efforts targeted specifically at A O displacement are currently limitedCognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule A O displacing therapeuticsCognition Therapeutics has discovered two CNS drug like series of A O displacing compoundsAnalogs of both series displace oligomers from neurons and completely block A O induced membrane trafficking changes and synapse lossMembers of these series are highly brain penetrant and completely block oligomer induced memory deficits in Alzheimer s disease mouse modelsDrug candidate CTfrom Seriesis progressing through clinical trialsCognition now seeks to leverage the accumulated knowledge of SAR from both series plus the known sigmareceptor binding modulators to define and develop new lead candidates for the clinical pipelineAdditional candidates with different physicochemical and structural properties would de risk the clinical development to NDA process for these first in class treatmentsThis proposal will allow us to expand our portfolio of A O displacing molecules with the goal of identifying orally efficacious candidates for further development as therapeutics for AD Project Narrative Cognition Therapeutics Incs mission is to develop effective therapeutics for Alzheimer s disease which target the toxic Abeta oligomerA OproteinIn contrast to other A O intervention strategieswhich either block the expression of Abeta or clear A Os or block their formationCognition TherapeuticsCogRxhas chosen a noveloligomer displacementapproach to targeting A Osusing compounds to displace oligomers from their binding site on neuronal synapsesThis approach protects neurons from toxic oligomer assault and allows them to regenerate lost synapsesWe have discovered and developed two orally available CNS drug like lead series of sigmareceptor modulators that displace the A O protein from neuronal cells in the brainAnalogs from both series prevent memory deficits in Alzheimer s disease mouse modelsThis proposal requests funding in order to discover and develop new leads for the clinical pipelineleveraging our accumulated knowledge of the structure activity relationships of both series as well as known sigmareceptor modulatorsSuccessful advancement of a A O displacing drug would significantly impact the lives of themillion patients worldwide suffering from AD and MCIfor whom no disease modifying treatment exists